Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
  • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
  • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

• MCTs are relatively small and, once hydrolyzed, the fatty acids formed from MCTs are ionizable at physiological pH, and hence are generally soluble in aqueous solutions.
• the disclosure relates to a liquid pharmaceutical composition
• a liquid pharmaceutical composition comprising at least about 30 % by weight of the total composition of caprylic triglyceride, and one or more emulsion forming excipients present at a concentration sufficient to form stable emulsion for at least one month under ambient conditions.
• the caprylic triglyceride is present in an amount of between about 30% and about 60% by weight of the total composition.
• the purity of the caprylic triglyceride is at least 95%.
• the one or more emulsion forming excipients are selected from the group consisting of lecithin (e.g., Phospholipon 90G), hydrogenated castor oils including Polyoxyl 40 castor oil (e.g., Kolliphor RH40), caprylate esters, sodium oleate, glycerol, citric acid esters of monoglycerides and diglycerides (e.g., Citrem), monoglycerides and diglycerides of fatty acids including Propylene Glycol Monocaprylate (e.g.
• the one or more emulsion forming excipients are selected from the group consisting of lecithin, Kolliphor RH40, caprylate ester emulsifiers, and combinations thereof. In some aspects, the one or more emulsion forming excipients are selected from the group consisting of lecithin, sodium oleate, glycerol, and combinations thereof. In some aspects, the one or more emulsion forming excipients are selected from the group consisting of Citrem, monoglycerides and diglycerides of fatty acids, and combinations thereof.
• the one or more emulsion forming excipients are present in an amount of between about 1% and about 10% by weight of the total composition, preferably in an amount of between about 1% and about 8% by weight of the total composition.
• there are at least two emulsion forming excipients present in the composition and at least one of the emulsion forming excipients is present in an amount of at least 2.0% by weight of the total composition.
• the at least two emulsion forming excipients are present at a 1:1 to 2:1 ratio, relative to one another.
• the liquid pharmaceutical composition of the disclosure forms an emulsion that is stable for at least about one month at ambient conditions.
• the stable emulsions exhibits an average particle diameter of less than 0.5 ⁇ m for at least one month at ambient conditions, preferrable less than 0.3 ⁇ m for at least one month at ambient conditions, preferrable less than 0.2 ⁇ m for at least one month at ambient conditions.
• the emulsions may have a mean particle diameter of less than about 1000 nm, but greater than about 100 nm, e.g. between about 100 nm and 500 nm, between about 200 nm and about 300 nm, between about 160 nm and about 190 nm, etc.
• the liquid pharmaceutical composition of the disclosure further comprises an oil soluble flavouring agent.
• the disclosure relates to methods of treating a disease or disorder associated with reduced cognitive function in a subject in need thereof, the method comprising administering to the subject a liquid pharmaceutical composition of the disclosure in an amount effective to elevate ketone body concentrations in said subject to thereby treat said disease or disorder.
• the disease or disorder associated with reduced cognitive function is selected from Alzheimer’s disease and Age-Associated Memory Impairment.
• FIG.1 illustrates an exemplary method for preparation of liquid pharmaceutical compositions of the disclosure.
• FIG. 2 illustrates exemplary components, concentrations and compositions of liquid pharmaceutical compositions, in accordance with embodiments of the disclosure.
• FIG. 3 illustrates a region of optimized performing compositions of liquid pharmaceutical compositions of FIG.2, in accordance with embodiments of the disclosure.
• FIG. 4 illustrates performance of compositions of liquid pharmaceutical compositions of FIG.2, in accordance with embodiments of the disclosure.
• FIG 5 illustrates performance of compositions of liquid pharmaceutical compositions of FIG.2, in accordance with embodiments of the disclosure.
• FIG. 6 illustrates performance of compositions of liquid pharmaceutical compositions of FIG.2, in accordance with embodiments of the disclosure.
• FIG. 7. illustrates exemplary particle size distributions for different Citrem formulations, in accordance with embodiments of the disclosure.
• FIG. 8 illustrates stability results for Oleate formulations, in accordance with embodiments of the disclosure.
• FIG.9 illustrates visual stability results for Oleate formulations, in accordance with embodiments of the disclosure.
• FIG. 10 illustrates stability results for Oleate formulations, in accordance with embodiments of the disclosure. [0024] FIG.
• FIG. 11 illustrates stability results for Oleate formulations, in accordance with embodiments of the disclosure.
• FIG.12 illustrates visual stability results for Oleate formulations, in accordance with embodiments of the disclosure.
• FIG. 13 illustrates stability results for Oleate formulations, in accordance with embodiments of the disclosure.
• FIG. 14 illustrates stability results for Oleate formulations, in accordance with embodiments of the disclosure.
• FIG.15 illustrates visual stability results for Oleate formulations, in accordance with embodiments of the disclosure.
• FIG. 16 illustrates stability results for Oleate formulations, in accordance with embodiments of the disclosure.
• FIG. 17 illustrates stability results for Oleate formulations, in accordance with embodiments of the disclosure.
• FIG.18 illustrates visual stability results for Oleate formulations, in accordance with embodiments of the disclosure.
• FIG. 19 illustrates stability results for Oleate formulations, in accordance with embodiments of the disclosure.
• FIG. 20 illustrates exemplary particle size distributions for different formulations of gamma-irradiated vs retention samples, in accordance with embodiments of the disclosure.
• FIGS21A-21J illustrate exemplary particle size distributions for lead formulations over time, in accordance with embodiments of the disclosure.
• FIG.22A illustrates pharmacokinetic parameters, including total ketone Cmax and
• FIG. 22B illustrates total ketone AUC for lead formulations, in accordance with embodiments of the disclosure.
• MCT Medium Chain Triglyceride
• LCTs Long Chain Triglycerides
• MCFAs medium chain fatty acids
• MCTs are ingested, they are first processed by lipases, which cleave the fatty acid chains from the glycerol backbone.
• MCFAs long chain fatty acids derived from normal dietary fat are re-esterified into LCTs and packaged into chylomicrons for transport in the lymph. This greatly slows the metabolism of LCTs relative to MCTs.
• LCFAs undergo little oxidation in the liver, due mainly to the inhibitory effects of malonyl-CoA.
• malonyl-CoA is produced as an intermediate in lipogenesis.
• Malonyl-CoA allosterically inhibits carnitine palmitoyltransferase I, and thereby inhibits LCFA transport into the mitochondria. This feedback mechanism prevents futile cycles of lipolysis and lipogenesis.
• MCFAs are, to a large extent, immune to the regulations that control the oxidation of LCFAs.
• MCFAs enter the mitochondria without the use of carnitine palmitoyltransferase I, therefore MCFAs by-pass this regulatory step and are oxidized regardless of the metabolic state of the organism.
• MCFAs since MCFAs enter the liver rapidly and are quickly oxidized, large amounts of ketone bodies are readily produced from MCFAs. As such, a large oral dose of MCTs (e.g., about 20 mL to 40 mL) will result in sustained hyperketonemia.
• the present disclosure generally relates to liquid pharmaceutical compositions comprising a high loading of at least one MCT, and methods of making and using such compositions.
• the liquid pharmaceutical compositions form a stable liquid emulsion in an aqueous use environment, e.g., in water or when administered to an aqueous use environment.
• the MCT is caprylic triglyceride, as described herein.
• the liquid pharmaceutical formulations may be “preservative free”.
• the formulation may form a stable liquid emulsion that maintains sterility (i.e., sufficient bio-burden reduction to allow for pharmaceutical use) for at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months at ambient conditions without the use of preservatives.
• the pharmaceutical compositions of the disclosure are a liquid pharmaceutical composition comprising a high drug loading of an MCT, e.g., caprylic triglyceride, and one or more emulsion forming excipients present at a concentration sufficient to form an emulsion at ambient conditions.
• the pharmaceutical compositions may comprise the components in amounts as described herein.
• the composition may form a stable liquid emulsion at ambient conditions, e.g., for at least 1 day, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, etc.
• the emulsions of the disclosure may generally be formed by high shear mixing or “high pressure homogenization, as is understood in the art.
• the pharmaceutical compositions of the disclosure may form a stable liquid emulsion at ambient conditions.
• An emulsion refers to a composition which, when diluted with water or other aqueous medium and gently mixed, yields a stable oil/water emulsion with a mean particle size of less than about 1 ⁇ m, but greater than about 100 nm, (i.e., 0.1-1 ⁇ m) and which is generally polydisperse.
• Such an emulsion is stable, meaning there is no visibly detectable phase separation and that there is no visibly detectable crystallization.
• the pharmaceutical composition of the disclosure forms an emulsion that is stable for at least about one month at ambient conditions.
• the stable emulsions exhibits an average particle diameter of less than 0.5 ⁇ m for at least one month at ambient conditions, preferrable less than 0.3 ⁇ m for at least one month at ambient conditions, preferrable less than 0.2 ⁇ m for at least one month at ambient conditions.
• the emulsions may have a mean particle diameter of less than about 1000 nm, but greater than about 100 nm, e.g. between about 100 nm and 500 nm, between about 200 nm and about 300 nm, between about 160 nm and about 190 nm, etc.
• the pharmaceutical compositions of the disclosure form stable emulsions in an aqueous use environment, e.g., in water, pharmaceutically suitable aqueous solution, or when administered in vivo.
• the emulsions may be stable at ambient conditions for at least about 24 hours, for at least 1 day, at least 1 month, at least 2 months, at least 3 months, at least 6 months, at least 12 months, etc.
• the emulsion formed does not phase separate for the duration of stability.
• the emulsions may have a mean particle diameter of less than about 1 ⁇ m, but greater than about 100 nm, (i.e., 0.1-1 ⁇ m).
• the emulsion formed may be stable at stomach pH, e.g., at a pH of about 1 to about 3, about 1.2 to 2.9, etc. In certain embodiments, the emulsion formed may be stable at intestinal and/or colon pH, e.g., at a pH of about 5 to about 7, about 5.5 to about 6.9, etc. In certain embodiments, the emulsion formed may begin to break down or phase separate at stomach pH after about 1 ⁇ 2 to about 1 hour, but does not release the encapsulated MCT until intestinal or colon pH.
• in-vitro digestion assays indicate that encapsulated MCT is released from emulsion at intestinal and/or colon pH, which is the primary location of lipid digestion enzymes.
• preferential release of MCT in the intestines and/or colon rather than the stomach may increase bioavailability of the MCT given the location of lipid digestion enzymes in these areas.
• the pharmaceutical compositions provide for preferential release of the high drug loading of MCT in the lower gastrointestinal tract of a user.
• preferential release of MCT in the lower gastrointestinal tract, including the colon may provide reduced stomach upset and related adverse events as compared to standard administration of non-formulated MCT oil.
• the improved bioavailability of the MCT may generally lead to increased ketone body production in vivo, as compared to standard administration of non-formulated MCT oil.
• the pharmaceutical compositions may include a high drug load of at least one MCT, such as caprylic triglyceride, of at least about 20% of the total composition, at least about 25% of the total composition, at least about 30% by weight of the total composition, at least about 40% by weight of the total composition, about 30% by weight of the total composition to about 65% by weight of the total composition, about 30% by weight of the total composition to about 60% by weight of the total composition, about 40% by weight of the total composition to about 50% by weight of the total composition, about 40% by weight of the total composition to about 45% by weight of the total composition, etc.
• MCT caprylic triglyceride
• MCTs refer to any glycerol molecule ester- linked to three fatty acid molecules, each fatty acid molecule having a carbon chain of 5-12 carbons.
• the pharmaceutical compositions may comprise an MCT represented by the following general formula: wherein R1, R2 and R3 are fatty acids having 5-12 carbons in the carbon backbone esterified to the a glycerol backbone.
• the MCTs of the disclosure may be prepared by any process known in the art, such as direct esterification, rearrangement, fractionation, transesterification, or the like.
• Sources of the MCT include any suitable source, semi-synthetic, synthetic or natural.
• MCT natural sources of MCT
• plant sources such as coconuts and coconut oil, palm kernels and palm kernel oils, and animal sources such as milk from any of a variety of species, e.g., goats.
• the lipids may be prepared by the rearrangement of a vegetable oil such as coconut oil. The length and distribution of the chain length may vary depending on the source oil.
• MCT containing 1-10% C6, 30-60% C8, 30-60% C10, 1-10% C10 are commonly derived from palm and coconut oils.
• the pharmaceutical compositions of the disclosure may comprise MCTs that have greater than about 95% C8 at R1, R2 and R3, and are herein referred to herein as caprylic triglyceride (“CT”).
• CT caprylic triglyceride
• exemplary sources of CT include MIGLYOL® 808 or NEOBEE® 895.
• CT may be obtained from coconut or palm kernel oil, made by semi-synthetic esterification of octanoic acid to glycerin, etc.
• the pharmaceutical compositions may comprise MCTs wherein R 1, R 2, and R 3 are fatty acids containing a six-carbon backbone (tri-C6:0).
• Tri-C6:0 MCT are absorbed very rapidly by the gastrointestinal tract in a number of animal model systems. The high rate of absorption results in rapid perfusion of the liver, and a potent ketogenic response.
• the pharmaceutical compositions may comprise MCTs wherein R 1, R 2, and R 3 are fatty acids containing an eight-carbon backbone (tri-C8:0).
• the pharmaceutical compositions may comprise MCTs wherein R 1, R 2, and R3 are fatty acids containing a ten-carbon backbone (tri-C10:0).
• the pharmaceutical compositions may comprise MCTs wherein R 1, R 2, and R 3 are a mixture of C8:0 and C10:0 fatty acids.
• the pharmaceutical compositions may comprise MCTs wherein R1, R2 and R3 are a mixture of C6:0, C8:0, C10:0, and C12:0 fatty acids.
• the pharmaceutical compositions may comprise MCTs wherein greater than 95% of R1, R2 and R3 are 8 carbons in length.
• the pharmaceutical compositions may comprise MCTs wherein the R1, R2, and R3 carbon chains are 6-carbon or 10-carbon chains.
• the pharmaceutical compositions may comprise MCTs wherein about 50% of R1, R2 and R3 are 8 carbons in length and about 50% of R1, R2 and R3 10 carbons in length.
• the pharmaceutical compositions may comprise MCTs wherein R1, R2 and R3 are 6, 8, 10 or 12 carbon chain length, or mixtures thereof.
• the liquid pharmaceutical formulations of the disclosure include one or more emulsion forming excipients.
• the one or more emulsion forming excipients may be any emulsifier capable of forming an emulsion with MCT oil.
• lecithin e.g., Phospholipon 90G
• hydrogenated castor oils including Polyoxyl 40 castor oil (e.g., Kolliphor RH40)
• caprylate esters sodium oleate, glycerol
• citric acid esters of monoglycerides and diglycerides e.g., Citrem
• monoglycerides and diglycerides of fatty acids including Propylene Glycol Monocaprylate (e.g. Capmul PG-8), and combinations thereof.
• the emulsion forming excipient(s) may be present in amounts sufficient to provide desired emulsion formation.
• the emulsion forming excipient may be present in an amount of between about 1% and about 10%, between about 1% and about 8% by weight of the total composition, between about 1.3% and about 10%, etc., by weight of the total composition.
• there are at least two emulsion forming excipients present in the composition and at least one of the emulsion forming excipients is present in an amount of at least 2.0% by weight of the total composition.
• the at least two emulsion forming excipients are present at a 1:1 to 2:1 ratio, relative to one another.
• the emulsion forming excipients may include various combinations of lecithin, Kolliphor RH40, and caprylate ester emulsifiers, and optionally glycerol. In other embodiments, the emulsion forming excipients may include various combinations of lecithin, sodium oleate, and optionally glycerol. In yet other embodiments, the emulsion forming excipients may include Citrem alone or in combination with monoglycerides and diglycerides of fatty acids. [0056] In certain embodiments, the liquid pharmaceutical formulations of the disclosure may optionally include one or more flavouring or sweetener agents.
• the flavouring or sweetening agent may be present in an amount of between 0.025% to 0.3%, between 0.15% to 0.3%, 0.5% for sweetening agent, 0.3% for flavouring agent, etc. by weight of the total composition.
• sucralose, stevia or similar sweetening agents may be used, with sucralose being preferred.
• vanilla, mango, berry, or similar flavouring agents may be used, with vanilla being preferred.
• the flavouring or sweetening agents may be oil soluble.
• suitable lecithin useful as an emulsion forming excipient of the disclosure may be derived from any suitable source, e.g., egg or soy.
• suitable lecithin may be selected from Soy PC, 95%, Avanti Number 441601; Egg PC, 95%, Avanti Number 131601; etc.
• Any suitable monoglyceride or diglyceride of fatty acids may be used as an emulsion forming agent of the disclosure, e.g., citric acid esters of mono and diglycerides of fatty acids (Citrem) E472C; mono and diglycerides of fatty acids E471; etc.
• Any suitable method for making the pharmaceutical compositions of the disclosure may be used. In certain aspects of the disclosure, it has been found that reproducibility and emulsion stability may be controlled by modifying manufacturing process as illustrated in the examples herein.
• the disclosure relates to methods of treating a disease or disorder associated with reduced cognitive function in a subject in need thereof, the method comprising administering to the subject a pharmaceutical composition of the disclosure in an amount effective to elevate ketone body concentrations in said subject to thereby treat said disease or disorder.
• the pharmaceutical composition of the disclosure may be administered outside of the context of a ketogenic diet.
• carbohydrates may be consumed at the same time as pharmaceutical compositions disclosed herein.
• diseases and disorders associated with reduced cognitive function include Age-Associated Memory Impairment (AAMI), Alzheimer’s Disease (AD), Parkinson’s Disease, Friedreich’s Ataxia (FRDA), GLUT1-deficient Epilepsy, Leprechaunism, and Rabson-Mendenhall Syndrome, Coronary Arterial Bypass Graft (CABG) dementia, anesthesia-induced memory loss, Huntington’s Disease, migraine and related headaches, and many others.
• AAMI Age-Associated Memory Impairment
• AD Alzheimer’s Disease
• FRDA Friedreich’s Ataxia
• GLUT1-deficient Epilepsy Leprechaunism
• Rabson-Mendenhall Syndrome coron-Mendenhall Syndrome
• CABG Coronary Arterial Bypass Graft
• the patient has or is at risk of developing disease-related reduced cognitive function caused by reduced neuronal metabolism, for example, reduced cognitive function associated with Alzheimer’s Disease (AD), Parkinson’s Disease, Friedreich’s Ataxia (FRDA), GLUT1-deficient Epilepsy, Leprechaunism, and Rabson- Mendenhall Syndrome, Coronary Arterial Bypass Graft (CABG) dementia, anesthesia-induced memory loss, Huntington’s Disease, and many others.
• AD Alzheimer’s Disease
• FRDA Friedreich’s Ataxia
• GLUT1-deficient Epilepsy Leprechaunism
• Rabson- Mendenhall Syndrome corretion Arterial Bypass Graft
• CABG Coronary Arterial Bypass Graft
• Huntington’s Disease Huntington’s Disease
• reduced neuronal metabolism refers to all possible mechanisms that could lead to a reduction in neuronal metabolism.
• Such mechanisms include, but are not limited to mitochondrial dysfunction, free radical attack, generation of reactive oxygen species (ROS), ROS-induced neuronal apoptosis, defective glucose transport or glycolysis, imbalance in membrane ionic potential, dysfunction in calcium flux, and the like.
• ROS reactive oxygen species
• high blood ketone levels will provide an energy source for brain cells that have compromised glucose metabolism, leading to improved performance in cognitive function.
• subject and patient are used interchangeably, and refer to any mammal, including humans that may benefit from treatment of disease and conditions associated with or resulting from reduced neuronal metabolism.
• Effective amount refers to an amount of a compound, material, or pharmaceutical composition, as described herein that is effective to achieve a particular biological result.
• Effectiveness for treatment of the aforementioned conditions may be assessed by improved results from at least one neuropsychological test.
• neuropsychological tests are known in the art and include Clinical Global Impression of Change (CGIC), Rey Auditory Verbal Learning Test (RAVLT), First-Last Names Association Test (FLN), Telephone Dialing Test (TDT), Memory Assessment Clinics Self-Rating Scale (MAC-S), Symbol Digit Coding (SDC), SDC Delayed Recall Task (DRT), Divided Attention Test (DAT), Visual Sequence Comparison (VSC), DAT Dual Task (DAT Dual), Mini-Mental State Examination (MMSE), and Geriatric Depression Scale (GDS), among others.
• CGIC Clinical Global Impression of Change
• RAVLT Rey Auditory Verbal Learning Test
• FLN First-Last Names Association Test
• TTT Telephone Dialing Test
• MAC-S Memory Assessment Clinics Self-Rating Scale
• SDC SDC Delayed Recall Task
• DAT Divided Attention Test
• VSC
• cognitive function refers to the special, normal, or proper physiologic activity of the brain, including, without limitation, at least one of the following: mental stability, memory/recall abilities, problem solving abilities, reasoning abilities, thinking abilities, judging abilities, capacity for learning, perception, intuition, attention, and awareness.
• Enhanced cognitive function or “improved cognitive function” refers to any improvement in the special, normal, or proper physiologic activity of the brain, including, without limitation, at least one of the following: mental stability, memory/recall abilities, problem solving abilities, reasoning abilities, thinking abilities, judging abilities, capacity for learning, perception, intuition, attention, and awareness, as measured by any means suitable in the art.
• the methods of the present invention further comprise determination of the patients’ genotype or particular alleles.
• the patient's alleles of the apolipoprotein E gene are determined. It has been found that non-E4 carriers performed better than those with the E4 allele when elevated ketone body levels were induced with MCT. Also, those with the E4 allele had higher fasting ketone body levels and the levels continued to rise at the two hour time interval. Therefore, E4 carriers may require higher ketone levels or agents that increase the ability to use the ketone bodies that are present.
• the pharmaceutical compositions of the disclosure are administered orally.
• Therapeutically effective amounts of the therapeutic agents can be any amount or dose sufficient to bring about the desired effect and depend, in part, on the severity and stage of the condition, the size and condition of the patient, as well as other factors readily known to those skilled in the art.
• the dosages can be given as a single dose, or as several doses, for example, divided over the course of several weeks, as discussed elsewhere herein.
• the pharmaceutical compositions of the disclosure in one embodiment, are administered in a dosage required to increase blood ketone bodies to a level required to treat and/or prevent the occurrence of any disease- or age-associated cognitive decline, such as AD, AAMI, and the like.
• oral administration of a pharmaceutical composition of the disclosure results in hyperketonemia.
• Hyperketonemia in one embodiment, results in ketone bodies being utilized for energy in the brain even in the presence of glucose. Additionally, hyperketonemia results in a substantial (39%) increase in cerebral blood flow (Hasselbalch, S.G., et al., Changes in cerebral blood flow and carbohydrate metabolism during acute hyperketonemia, Am J Physiol, 1996, 270:E746-51).
• Hyperketonemia has been reported to reduce cognitive dysfunction associated with systemic hypoglycemia in normal humans (Veneman, T., et al., Effect of hyperketonemia and hyperlacticacidemia on symptoms, cognitive dysfunction, and counterregulatory hormone responses during hypoglycemia in normal humans, Diabetes, 1994, 43:1311-7). Please note that systemic hypoglycemia is distinct from the local defects in glucose metabolism that occur in any disease- or age- associated cognitive decline, such as AD, AAMI, and the like. [0072] Administration can be on an as-needed or as-desired basis, for example, once- monthly, once-weekly, daily, or more than once daily.
• compositions provided herein are, in one embodiment, intended for “long term” consumption, sometimes referred to herein as for ‘extended’ periods. “Long term” administration as used herein generally refers to periods in excess of one month. Periods of longer than two, three, or four months comprise one embodiment of the instant invention. Also included are embodiments comprising more extended periods that include longer than 5, 6, 7, 8, 9, or 10 months.
• Periods in excess of 11 months or 1 year are also included. Longer terms use extending over 1, 2, 3 or more years are also contemplated herein. “Regular basis” as used herein refers to at least weekly, dosing with or consumption of the compositions. More frequent dosing or consumption, such as twice or thrice weekly are included. Also included are regimens that comprise at least once daily consumption.
• regimens that comprise at least once daily consumption.
• the skilled artisan will appreciate that the blood level of ketone bodies, or a specific ketone body, achieved may be a valuable measure of dosing frequency. Any frequency, regardless of whether expressly exemplified herein, that allows maintenance of a blood level of the measured compound within acceptable ranges can be considered useful herein.
• dosing frequency will be a function of the composition that is being consumed or administered, and some compositions may require more or less frequent administration to maintain a desired blood level of the measured compound (e.g., a ketone body).
• Administration can be carried out on a regular basis, for example, as part of a treatment regimen in the patient.
• a treatment regimen may comprise causing the regular ingestion by the patient of a pharmaceutical composition of the disclosure in an amount effective to enhance cognitive function, memory, and behavior in the patient. Regular ingestion can be once a day, or two, three, four, or more times per day, on a daily or weekly basis.
• regular administration can be every other day or week, every third day or week, every fourth day or week, every fifth day or week, or every sixth day or week, and in such a regimen, administration can be multiple times per day.
• the goal of regular administration is to provide the patient with optimal dose of a pharmaceutical composition of the disclosure, as exemplified herein.
• Dosages of the inventive compositions such as, for example, those comprising MCT, may be administered in an effective in an effective amount to increase the cognitive ability of patients afflicted with diseases of reduced neuronal metabolism, such as in patients with any disease- or age-associated cognitive decline, such as, AD, AAMI, and the like.
• the inventive compositions result in elevating ketone concentrations in the body, and in this embodiment, the compositions are administered in an amount that is effective to induce hyperketonemia.
• hyperketonemia results in ketone bodies being utilized for energy in the brain.
• the composition increases the circulating concentration of at least one type of ketone body in the mammal or patient.
• the circulating ketone body is D-beta-hydroxybutyrate. The amount of circulating ketone body can be measured at a number of times post administration, and in one embodiment, is measured at a time predicted to be near the peak concentration in the blood, but can also be measured before or after the predicted peak blood concentration level.
• Measured amounts at these off-peak times are then optionally adjusted to reflect the predicted level at the predicted peak time.
• the predicted peak time is at about two hours. Peak circulating blood level and timing can vary depending on factors known to those of skill in the art, including individual digestive rates, co-ingestion or pre- or post-ingestion of foods, drinks, etc., as known to one of skill in the art.
• the peak blood level reached of D-beta-hydroxybutyrate is between about 0.05 millimolar (mM) to about 50 mM.
• Another way to determine whether blood levels of D-beta-hydroxybutyrate are raised to about 0.05 to about 50 mM is by measurement of D-beta-hydroxybutyrate urinary excretion a range in the range of about 5 mg/dL to about 160 mg/dL.
• the peak blood level is raised to about 0.1 to about 50 mM, from about 0.1 to about 20 mM, from about 0.1 to about 10 mM, to about 0.1 to about 5 mM, more preferably raised to about 0.15 to about 2 mM, from about 0.15 to about 0.3 mM, and from about 0.2 to about 5 mM, although variations will necessarily occur depending on the formulation and host, for example, as discussed above.
• the peak blood level reached of D-beta-hydroxybutyrate will be at least about 0.05 mM, at least about 0.1 mM, at least about 0.15 mM, at least about 0.2 mM, at least about 0.5 mM, at least about 1 mM, at least about 1.5 mM, at least about 2 mM, at least about 2.5 mM, at least about 3 mM, at least about 4 mM, at least about 5 mM, at least about 10 mM, at least about 15 mM, at least about 20 mM, at least about 30 mM, at least about 40 mM, and at least about 50 mM.
• the MCT dose in one embodiment, is in the range of about 0.05 g/kg/day to about 10 g/kg/day of MCT. In other embodiments, the dose will be in the range of about 0.25 g/kg/day to about 5 g/kg/day of MCT.
• the dose will be in the range of about 0.5 g/kg/day to about 2 g/kg/day of MCT. In other embodiments, the dose will be in the range of about 0.1 g/kg/day to about 2 g/kg/day.
• the dose of MCT is at least about 0.05 g/kg/day, at least about 0.1 g/kg/day, at least about 0.15 g/kg/day, at least about 0.2 g/kg/day, at least about 0.5 g/kg/day, at least about 1 g/kg/day, at least about 1.5 g/kg/day, at least about 2 g/kg/day, at least about 2.5 g/kg/day, at least about 3 g/kg/day, at least about 4 g/kg/day, at least about 5 g/kg/day, at least about 10 g/kg/day, at least about 15 g/kg/day, at least about 20 g/kg/day, at least about 30 g/kg/day, at least about 40 g/kg/day, and at least about 50 g/kg/day.
• the present compositions are provided as a liquid formulation for administration to a subject in need thereof.
• the compositions may be advantageously combined and/or used in combination with other therapeutic or prophylactic agents, different from the disclosed MCT compounds.
• administration in conjunction with the subject compositions enhances the efficacy of such agents.
• the compounds may be advantageously used in conjunction with antioxidants, compounds that enhance the efficiency of glucose utilization, and mixtures thereof.
• the daily dose of MCT can also be measured in terms of grams of MCT per kg of body weight (BW) of the mammal.
• BW body weight
• the daily dose of MCT can range from about 0.01 g/kg to about 10.0 g/kg BW of the mammal.
• the daily dose of MCT is from about 0.1 g/kg to about 5 g/kg BW of the mammal. More preferably, the daily dose of MCT is from about 0.2 g/kg to about 3 g/kg of the mammal. Still more preferably, the daily dose of MCT is from about 0.5 g/kg to about 2 g/kg of the mammal.
• exemplary liquid emulsions of the disclosure may be made according to the procedure illustrated in Figure 1, with modifications as may be appropriate and understood by those of skill in the art.
• particle size testing methods that may be used are as follows: Procedure 1. Background measurement is performed with pure dispersant (milliQ-H 2 O) 2. Vortex emulsion sample and add aliquots to dispersant with a pipette until the obscuration is within optimal range (5 – 15). The required volume is typically 10-100 ⁇ L depending on particle size with more volume required for smaller particle sizes.
• liquid compositions of the disclosure may be formulated with combinations of emulsion forming agents such as Phospholipon 90G (Soy Lecithin), Kolliphor RH40 ((PEG-40 Hydrogenated Castor Oil), and Capmul PG-8 ((Propylene glycol monocaprylate).
• Phospholipon 90G Soy Lecithin
• Kolliphor RH40 (PEG-40 Hydrogenated Castor Oil)
• Capmul PG-8 (Propylene glycol monocaprylate).
• Exemplary manufacturing methods for such formulations are generally as provided in Figure 1 and are summarized in the table below:
• Exemplary emulsion forming agent concentrations are provided in Figure 2, and stability results are shown in the table below and in Figure 3.
• Combinations of Phospholipon 90G, Kollipohor RH40 and Capmul PG-8 [0088] It was found that combinations and concentrations indicated in the circled portion of lower right-hand corner of Figure 3 were found to be the most stable formulations. Equal mix of Phospholipon 90 G, Kolliphor RH40 and Capmul PG-8 was also very stable.
• Particle size evolution of Phospholipon 90G, Kolliphor RH40, Capmul PG-8 emulsions prepared via Ultra Turrax emulsification are shown in Figure 4, and particle size evolution of Phospholipon 90G, Kolliphor RH40, Capmul PG-8 emulsions: prepared via Silverson & High Pressure Homogeniser emulsification are shown in Figure 5.
• Visual appearance of Phospholipon 90G, Kolliphor RH40, Capmul PG-8 emulsions under a 1 month stability study are shown in Figure 6.
• Caprylic acid was detected in 50% Tricaprylin, 2% Phospholipon 90 G, 2% Kolliphor RH40, 2% Capmul PG-8 sample at one month. Reducing total emulsifier concentration to 4% in the 50% Tricaprylin, 2.67% Phospholipon 90G, 1.33% Kolliphor RH40 only had a minor effect on initial particle size. [0093] In other examples, the impact of Kolliphor RH40 concentrations was investigated.
• liquid compositions of the disclosure may be formulated with combinations of emulsion forming agents such as Citrem and monoglycerides and diglycerides of fatty acids.
• Emulsions prepared include: 20% Tricaprylin, 0.8% Citrem, 0.5% monoglyceride in Citrate Buffer pH 6 (2 formulations made using emulsifiers from different suppliers); 20% Tricaprylin, 0.8% Citrem, 0.5% monoglyceride in milliQ-H20 pH 6; and 20% Tricaprylin, 0.8% Citrem, 0.5% monoglyceride in milliQ-H20 pH 6. Exemplary particle size distributions are shown in Figure 7. [0095] EXAMPLE 3 – Additional component combinations [0096] Additional investigations were performed to improve stability and MCT concentration.
• exemplary liquid formulations of the disclosure may be prepared from combinations of emulsion forming agents such as: Lecithin, sodium oleate and glycerol ratios at different MCT concentrations.
• the formulations were prepared by: Silverson vs High pressure homogenization.
• Sodium oleate had a slight destabilizing effect at pH7.
• Stability results for formulations prepared via a Silverson mixer are shown in Figure 8 (Stability results for 20% Tricaprylin, 2.4% Lecithin, varied Glycerol, varied Oleate), Figure 9 (Visual stability results for 20% Tricaprylin, 2.4% Lecithin, varied Glycerol, varied Oleate), Figure 10 (Stability results for 20% Tricaprylin, 1.6% Lecithin, varied Glycerol, varied Oleate), Figure 11(Stability results for 20% Tricaprylin, 6.0% Lecithin, varied Glycerol, varied Oleate, Figure 12(Visual stability results for 20% Tricaprylin, 6.0% Lecithin, varied Glycerol, varied Oleate, and Figure 13 (Stability results for 20% Tricaprylin, 4.0% Lecithin, varied Glycerol, varied Oleate).
• Stability results for formulations prepared via a High Pressure homogenation are shown in Figure 14 (Stability results for 20% Tricaprylin, 2.4% Lecithin, varied Glycerol, varied Oleate), Figure 15 (Visual stability results for 20% Tricaprylin, 2.4% Lecithin, varied Glycerol, varied Oleate), Figure 16 (Stability results for 20% Tricaprylin, 1.6% Lecithin, varied Glycerol, varied Oleate), Figure 17(Stability results for 20% Tricaprylin, 6.0% Lecithin, varied Glycerol, varied Oleate, Figure 18(Visual stability results for 20% Tricaprylin, 6.0% Lecithin, varied Glycerol, varied Oleate, and Figure 19 (Stability results for 20% Tricaprylin, 4.0% Lecithin, varied Glycerol, varied Oleate).
• EXAMPLE 5 – Bioburden Reduction Methods Methods for bioburden reduction of the formulations of the disclosure are provided below: [00105] As part of the development process, a series of bioburden reduction measures were evaluated for their effectiveness and potential to be incorporated into the manufacturing process. Details of the various studies performed are summarized below. [00106] Filtration [00107] Incorporation of filtration as a bioburden reduction step may be used as the simplest method of reducing bio load (if present). Filter compatibility studies were conducted by Pall Filtration, with evaluation of microbial retention of the selected filters conducted. These studies confirmed that selected formulations were sensitive to the type of filter media, and that the preferred media type was not microbially retentive.
• Heating is a commonly accepted method of reducing bio load. Evaluation of heat conditions commonly used to control microbial growth was attempted on exemplary formulations. All temperature conditions trialed showed significant disruption to the PSD profile of the product, confirming that the application of heat is not viable for bioburden control. This observation correlates with the deterioration of product due to elevated temperature observed in the development trials.
• Gamma irradiation is a commonly accepted method of sterilizing componentry and reducing bio load in natural materials. Exemplary formulations were irradiated at various dosages and then assessed for the impact of irradiation on product performance.
• Irradiated samples also showed no negative impact from gamma irradiation on the primary container and closures for all doses evaluated, i.e., seals were not observed to become brittle as a result of irradiation
• Samples irradiated at 15 and 25 kGy also showed no changes to appearance, assay and pH, however the related substance profile and particle size distribution were impacted at these doses. In this regard, particle size distribution of gamma-irradiated samples appear more affected than retention samples, results shown in Figure 20.
• EXAMPLE 7 –Longer Term Stability The following formulations of the disclosure and comparative formulations were prepared in accordance with the general methodology of Figure 1, as may be modified as required and understood by those of skill in the art. Exemplary longer term stability results are illustrated in the below tables.
• Sweetening Agent Three levels of sucralose (0.025%, 0.05% and 0.1%) and three levels of stevia (0.1%, 0.2% and 0.3%) were compared. No clear sweetening difference between sucralose and stevia was identified, as the flavouring agent predominates. However, sucralose is slightly preferred as it can be used at lower concentrations (i.e., 0.05% - 0.1% sucralose was found to provide a sufficient level of sweetness).
• Flavouring Agent [00125] Different flavouring agents were compared (at a 0.1% sucralose concentration). Concentrations were selected based on manufacturers recommendations and initial trials.
• FIG. 21A-21J illustrate particle size distribution at various time points for lead formulations AC-OLE-1 through AC-OLE-10, as indicated.
• EXAMPLE 11 – pK Study of Lead Formulations [00132] The lead formulations of Example 10 (AC-OLE-1 through AC-OLE-10) were administered to healthy volunteers to investigate pharmacokinetic effects of the liquid formulations of disclosure. [00133] The investigation will include several testing sites and cycles. At east site and in each cycle, several of the lead formulations (up to 4) will be tested on up to 20 healthy volunteers in a partial or full cross-over design. Once each cycle is completed, blood parameters will be analysed.

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